Pathogenesis Of Allograft Injury Research Articles

Plasma Donor-Derived Cell-Free DNA Levels Are Associated With the Inflammatory Burden and Macrophage Extracellular Trap Activity in Renal Allografts.

Recent studies have confirmed the role of plasma donor-derived cell-free DNA (ddcfDNA) as a reliable non-invasive biomarker for allograft injury after kidney transplantation. Whereas the variability of plasma ddcfDNA levels among recipients has limited their clinical use. This study aimed to explore the intrinsic factors associated with plasma ddcfDNA elevation by investigating the impact of Banff lesions and inflammatory infiltrates on ddcfDNA levels in kidney transplant recipients. From March 2017 to September 2019, a total of 106 kidney transplant recipients with matched allograft biopsies were included, consisting of 13 recipients with normal/nonspecific changes, 13 recipients with borderline changes, 60 with T cell-mediated rejection, and 20 with antibody-mediated rejection. Histologic classification was performed according to the Banff 2017 criteria by two experienced pathologists. Plasma ddcfDNA fractions ranged from 0.12% to 10.22%, with a median level of 0.91%. Banff histology subelements including glomerulitis, intimal arteritis, and severe interstitial inflammation were correlated with increased plasma ddcfDNA levels. The inflammatory cell infiltrate in the allografts was phenotyped by immunochemistry and automatically counted by digital image recognition. Pearson correlation analysis revealed a significant positive correlation between macrophage infiltrations in allografts and plasma ddcfDNA levels. Additionally, macrophage extracellular trap (MET) activity was significantly associated with the rise in plasma ddcfDNA levels. Our findings demonstrated that plasma ddcfDNA could reflect the inflammatory state in renal allografts and suggested the potential role of METs in the pathogenesis of allograft injury.

Poorer Outcomes for Recipients of Heart Allografts From HCV-Positive Donors

OVER THE PAST 30 YEARS, ORGAN TRANSPLANTAtion has evolved from an interesting experiment in human immunobiology to the most practical means of rehabilitating patients with end-stage dysfunction. At the same time, the requirement for chronic antirejection therapy, the presence of chronic or relapsing viral infection, and environmental exposures to a variety of opportunistic pathogens, have created a pathophysiological state and set of vulnerabilities rarely seen before. It has been estimated that 75% or more of organ transplant patients will have evidence of microbial replication and invasion in the first year posttransplant. Several principles have emerged from this experience. First, allograft rejection and invasive infection are closely linked, creating the need for a “therapeutic prescription” that has 2 components: an immunosuppressive program to prevent and treat rejection, and an antimicrobial strategy to make this safe. Changes in the immunosuppressive regimen should result in appropriate changes to the antimicrobial program. Second, bidirectional linkages between different processes are the rule, not the exception. Thus, hepatitis C virus (HCV) replication will increase the level of replication of cytomegalovirus (CMV) and vice versa, whereas CMV infection increases the incidence of Epstein-Barr virus–associated lymphoproliferative disease by a factor of 7 to 10. Third, perhaps the most important linkage is that in which viruses and allograft injury interact. The observation by Gasink and colleagues reported in this issue of JAMA that receipt of heart allografts from HCV-seropositive donors is associated with a poorer posttransplant survival is both expected and important. Expected because other viruses, such as CMV, appear to have this effect. Important because the chronic shortage of donors has resulted in attempts to expand the guidelines for accepting allografts, and there has been the hope that organs from HCV-positive donors could be used, particularly for critically ill organ recipients. The results of this study suggest that with current immunosuppressive therapy and antiviral prescription, the use of HCV-positive heart donors is not without hazard, even for HCV-positive recipients; that is, superinfection with HCV occurs, is clinically important, and cannot be generally recommended with current regimens of therapy. The question that emerges is whether special regimens can be developed that would allow the use of such organs with greater safety. In the meantime, the use of hearts from HCVpositive donors should be restricted to the critically ill who would not survive without an immediate transplant; whether such an approach is appropriate for other organs remains to be seen. The traditional view of the pathogenesis of allograft injury is that the triggering of a given pathway results in a unique histopathology. If a different pathway is involved, then the end result is a different histopathology that is recognizable. This so-called silo hypothesis was thought to provide insight into the pathogenesis of different clinical states. Compelling evidence now suggests that this view of pathogenesis is incorrect; rather than separate silos for each process, multiple paths exist that provide entrance into a final common pathway. Thus, such widely disparate processes as ischemia-reperfusion injury, immunologic injury, and certain infections (including HCV, CMV, and presumably other viruses such as human herpesvirus 6 and Epstein-Barr virus) can produce comparable histopathologic findings. The pattern of cytokine, chemokine, and growth factor release associated with each of these processes appears to be quite similar, thus explaining the final common pathway hypothesis. Similarly, the possibility of additive or synergistic effects due to multiple processes occurring simultaneously does not appear unreasonable. In addition, identification and control of these concomitant processes could improve the outcome in certain patients at risk for HCV-mediated processes. The clinical effect of HCV for patients undergoing organ transplantation can be divided into 2 general categories: the direct causation of acute and chronic liver injury, and the

CYTOMEGALOVIRUS INFECTION IN THE LIVER TRANSPLANT RECIPIENT: Epidemiology, Pathogenesis, and Clinical Management

The effects of cytomegalovirus (CMV) on the liver transplant patient can be divided into two general categories: the direct infectious disease effects (e.g. CMV mononucleosis, hepatitis, pneumonitis, GI infection) and the indirect effects that are mediated by cytokines elaborated as a consequence of the infection. These indirect effects include an immunosuppressive effect that contributes to the development of superinfection with fungi, bacteria, and Pneumocystis carinii; a role in the pathogenesis of allograft injury; and a role in the development of post-transplant lymphoproliferative disease. The two key steps in the pathogenesis of CMV infection-reactivation of the virus from latency and systemic spread-are modulated by the immunosuppressive therapy administered. New antiviral programs, primarily those involving ganciclovir, have resulted in considerable progress in the prevention and treatment of CMV disease among liver transplant recipients.

Leukotrienes in renal transplant rejection in rats. Distinct roles for leukotriene B4 and peptidoleukotrienes in the pathogenesis of allograft injury.

To investigate the role of leukotrienes in renal allograft rejection, we studied the effects of specific leukotriene inhibitors in a rat kidney transplant model. The enhanced renal production of leukotrienes observed in allograft recipients was reduced in a dose-dependent manner by the specific 5-lipoxygenase inhibitor MK886. This suppression of leukotriene production caused a substantial improvement in renal function. Inhibition of 5-lipoxygenase also reduced the severity of vascular inflammation and endothelial injury in allografts, and profoundly inhibited expression of donor MHC class II Ag on kidney cells. Survival of renal allograft recipients was prolonged from 10 +/- 1 days in controls to 16 +/- 1 days in animals that received a 6-day course of MK886 (p < 0.05). To investigate the relative roles of LTB4 compared to peptidoleukotrienes in these processes, we treated a separate group of animals with the specific peptidoleukotriene receptor antagonist SKF106203. This agent inhibits the interaction of peptidoleukotrienes with their receptor(s) but does not affect the biologic actions of LTB4. In these studies, SKF106203 caused a modest improvement in renal allograft function that was of lesser magnitude than that seen with the 5-lipoxygenase inhibitor. SKF106203 also reduced vascular inflammation in allografts, but had no effect on expression of MHC class II Ag. We conclude that leukotrienes play a key role in the pathogenesis of renal allograft rejection. Furthermore, the detrimental effects of leukotrienes in rejection are mediated by distinct actions of LTB4 and peptidoleukotrienes.